Cardiac conduction (Homo sapiens)

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32, 43, 759, 29, 54, 6549, 9236, 56, 62, 68, 71...27, 468517, 22, 2610, 11, 93, 10014, 4737, 5319, 924, 21, 25, 31, 3512, 16, 50, 876, 3828, 40, 7820, 94, 981, 3, 7, 30, 34...42, 452, 8, 15, 52, 61...13, 33, 39, 5855, 8918, 44, 59, 60, 707951, 73, 955, 23, 24, 48, 64...cytosolplatelet dense tubular network lumensarcoplasmic reticulum lumenNAD+ ASPH ATP1A2 FXYD4 ATP2A3 NPR1 CACNG2 CACNB1 KCNK5 SCN7A SCN2B CACNG8 CACNG8 Ca2+CACNA2D2(19-1001) NPPA genep-T287-CAMK2G KCNE1L Na+CACNG5 KCNK2 CACNG6 NAD+ K+LTCC heteropentamer(open)FGF14 TRDN KCNK16 CACNA2D4(20-991) CAMK2heteromer:CALM:4xCa2+SCN3B NPPC I(1,4,5)P3 ADPORAI1 SLC8A3 FKBP1B KCNIP1 KCND tetramer:KCNIPtetramerSCN11A RYR3 CACNG3 AHCYL1:NAD+p-T287-CAMK2D ATP2A1-3Ca2+SCN1A p-S23,S24-TNNI3NPR2 ATP1B3 Ca2+ITPR3 SLC8A2 KCNJ4 KCNK17 SLC8A1 KCNK dimersCACNA2D3(29-?) CACNG7 PRKACACACNA1S CACNA2D4(992-1137) AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerSCN4B RANGRFSCN3A Ca2+TNNI3KCND3 CACNB4 ATP2A2 K+ITPR3 ATP1A4 KCND1 ATP2B4 KCNQ1 Ca2+ ATP2B4DMPK dimerNPPA(1-25)CACNB1 SCN10A ATPKCNE1L ATP2B2 ITPR2 ATP2B1-4CACNG4 CASQ1 polymer NPPA(26-55)CACNA2D1(957-1103) KCNE2 AKAP9 TBX5:WWTR1:PCAFNPPA(124-151) ATP1A:ATP1B:FXYDATPCACNB3 I(1,4,5)P3 KCNIP3 NKX2-5:GATA4:HIPK1,2RYRtetramer:FKBP1Btetramer:CASQpolymer:TRDN:junctinCa2+K+CACNA2D2(1002-1150) KCNK7 CACNA2D4(992-1137) KCND2 FGF11-14PLN pentamerITPR1 CACNG7 KCNJ2 KAT2B CACNG1 NPR1 dimerCa2+AHCYL1 SLNCa2+SCN5A NOS1 HIPK1 LTCC heteropentamer(closed)IP3Rtetramer:I(1,4,5)P3:4xCa2+CALM1 K+NPPA(56-123)ORAI2 ATP2B3 KCNK9 ATP2B4:NOS1ATPATP2A1 CACNA2D1(25-956) CACNA2D2(1002-1150) KCNJ tetramerFGF11 KCNK12 p-T287-CAMK2B Na+ADPNPPA(124-151):NPR1dimerCa2+SCN8A SCN2A CACNG5 ITPR2 NPPA(124-151)NOS1Ca2+CACNA1F SCN1B KCNE4 CACNA2D3(29-?) SCNAs:SCNBsCa2+CACNA2D4(20-991) Na+ATP1B2 K+Na+NPR2KCNH2 CACNB2 FXYD2 CACNG3 STIM1:TRPC1ABCC9 SLC8A1,2,3KCNE3 NPPA(1-153)RYR1 ITPR1 KCNIP4 SCN4A KCNJ11 ITPR2 NPR1 FGF13 Ca2+ATP2B1 DMPK CACNG2 p-S16-PLN pentamerNKX2-5 ATPK+CACNA1C KCNK1 ATP1B1 ATP2B4 Ca2+CACNB4 KCNJ11:ABCC9H+KCNK18 KCNK3 FGF12 ATP1A3 KCNJ12 ITPR3 FXYD1 CACNA2D3(?-1091) KCNK13 AHCYL1 PiH2OCa2+Na+HIPK2 CACNA1C I(1,4,5)P3 SCN9A TBX5 CALM1TRPC1 K+KCNE3 CACNA1D WWTR1 FXYD7 SRICACNB3 CACNA2D2(19-1001) STIM1 KCNE1 ITPR:I(1,4,5)P3tetramerCACNA1F p-T286-CAMK2A STIM1 KCNJ14 Na+ATP1A1 KCNIP2 CACNB2 ITPR1 H+FXYD3 K+CACNA1S K+CACNA2D1(957-1103) Ca2+CACNG1 CLIC2CACNA1D CACNA2D1(25-956) I(1,4,5)P3GATA4 KCNK4 KCNE2 CASQ2 polymer NPPCCACNG4 FXYD6 p-S16-PLN Ca2+PLN NPR2:NPPCCACNG6 K+CACNA2D3(?-1091) RYR2 KCNE4 ADPCORIN(802-1042)Ca2+ KCNK6 KCNH2:KCNEKCNE1 CRAC channelKCNK15 AKAP9:KCNQ1tetramer:KCNE dimerKCNK10 3310, 84, 93, 9678


Description

The normal sequence of contraction of atria and ventricles of the heart require activation of groups of cardiac cells. The mechanism must elicit rapid changes in heart rate and respond to changes in autonomic tone. The cardiac action potential controls these functions. Action potentials are generated by the movement of ions through transmembrane ion channels in cardiac cells. Like skeletal myocytes (and axons), in the resting state, a given cardiac myocyte has a negative membrane potential. In both muscle types, after a delay (the absolute refractory period), K+ channels reopen and the resulting flow of K+ out of the cell causes repolarisation. The voltage-gated Ca2+ channels on the cardiac sarcolemma membrane are generally triggered by an influx of Na+ during phase 0 of the action potential. Cardiac muscle cells are so tightly bound that when one of these cells is excited the action potential spreads to all of them. The standard model used to understand the cardiac action potential is the action potential of the ventricular myocyte (Park & Fishman 2011, Grant 2009).

The action potential has 5 phases (numbered 0-4). Phase 4 describes the membrane potential when a cell is not being stimulated. The normal resting potential in the ventricular myocardium is between -85 to -95 mV. The K+ gradient across the cell membrane is the key determinant in the normal resting potential. Phase 0 is the rapid depolarisation phase in which electrical stimulation of a cell opens the closed, fast Na+ channels, causing a large influx of Na+ creating a Na+ current (INa+). This causes depolarisation of the cell. The slope of phase 0 represents the maximum rate of potential change and differs in contractile and pacemaker cells. Phase 1 is the inactivation of the fast Na+ channels. The transient net outward current causing the small downward deflection (the "notch" of the action potetial) is due to the movement of K+ and Cl- ions. In pacemaker cells, this phase is due to rapid K+ efflux and closure of L-type Ca2+ channels. Phase 2 is the plateau phase which is sustained by a balance of Ca2+ influx and K+ efflux. This phase sustains muscle contraction. Phase 3 of the action potential is where a concerted action of two outward delayed currents brings about repolarisation back down to the resting potential (Bartos et al. 2015). View original pathway at:Reactome.

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Reactome-Converter 
Pathway is converted from Reactome ID: 5576891
Reactome-version 
Reactome version: 65
Reactome Author 
Reactome Author: Jassal, Bijay

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  1. Cooper BJ, Key B, Carter A, Angel NZ, Hart DN, Kato M.; ''Suppression and overexpression of adenosylhomocysteine hydrolase-like protein 1 (AHCYL1) influences zebrafish embryo development: a possible role for AHCYL1 in inositol phospholipid signaling.''; PubMed Europe PMC Scholia
  2. Dekker JW, Budhia S, Angel NZ, Cooper BJ, Clark GJ, Hart DN, Kato M.; ''Identification of an S-adenosylhomocysteine hydrolase-like transcript induced during dendritic cell differentiation.''; PubMed Europe PMC Scholia
  3. Taske NL, Eyre HJ, O'Brien RO, Sutherland GR, Denborough MA, Foster PS.; ''Molecular cloning of the cDNA encoding human skeletal muscle triadin and its localisation to chromosome 6q22-6q23.''; PubMed Europe PMC Scholia
  4. Keane NE, Quirk PG, Gao Y, Patchell VB, Perry SV, Levine BA.; ''The ordered phosphorylation of cardiac troponin I by the cAMP-dependent protein kinase--structural consequences and functional implications.''; PubMed Europe PMC Scholia
  5. Ashpole NM, Herren AW, Ginsburg KS, Brogan JD, Johnson DE, Cummins TR, Bers DM, Hudmon A.; ''Ca2+/calmodulin-dependent protein kinase II (CaMKII) regulates cardiac sodium channel NaV1.5 gating by multiple phosphorylation sites.''; PubMed Europe PMC Scholia
  6. Tammaro P, Ashcroft FM.; ''A mutation in the ATP-binding site of the Kir6.2 subunit of the KATP channel alters coupling with the SUR2A subunit.''; PubMed Europe PMC Scholia
  7. Klugbauer N, Marais E, Hofmann F.; ''Calcium channel alpha2delta subunits: differential expression, function, and drug binding.''; PubMed Europe PMC Scholia
  8. Chou AC, Ju YT, Pan CY.; ''Calmodulin Interacts with the Sodium/Calcium Exchanger NCX1 to Regulate Activity.''; PubMed Europe PMC Scholia
  9. Shibata R, Misonou H, Campomanes CR, Anderson AE, Schrader LA, Doliveira LC, Carroll KI, Sweatt JD, Rhodes KJ, Trimmer JS.; ''A fundamental role for KChIPs in determining the molecular properties and trafficking of Kv4.2 potassium channels.''; PubMed Europe PMC Scholia
  10. Knappe S, Wu F, Masikat MR, Morser J, Wu Q.; ''Functional analysis of the transmembrane domain and activation cleavage of human corin: design and characterization of a soluble corin.''; PubMed Europe PMC Scholia
  11. Calderón-Rivera A, Andrade A, Hernández-Hernández O, González-Ramírez R, Sandoval A, Rivera M, Gomora JC, Felix R.; ''Identification of a disulfide bridge essential for structure and function of the voltage-gated Ca(2+) channel α(2)δ-1 auxiliary subunit.''; PubMed Europe PMC Scholia
  12. Babenko AP, Gonzalez G, Aguilar-Bryan L, Bryan J.; ''Reconstituted human cardiac KATP channels: functional identity with the native channels from the sarcolemma of human ventricular cells.''; PubMed Europe PMC Scholia
  13. Scannevin RH, Wang K, Jow F, Megules J, Kopsco DC, Edris W, Carroll KC, Lü Q, Xu W, Xu Z, Katz AH, Olland S, Lin L, Taylor M, Stahl M, Malakian K, Somers W, Mosyak L, Bowlby MR, Chanda P, Rhodes KJ.; ''Two N-terminal domains of Kv4 K(+) channels regulate binding to and modulation by KChIP1.''; PubMed Europe PMC Scholia
  14. Ceholski DK, Trieber CA, Young HS.; ''Hydrophobic imbalance in the cytoplasmic domain of phospholamban is a determinant for lethal dilated cardiomyopathy.''; PubMed Europe PMC Scholia
  15. Schroeder BC, Waldegger S, Fehr S, Bleich M, Warth R, Greger R, Jentsch TJ.; ''A constitutively open potassium channel formed by KCNQ1 and KCNE3.''; PubMed Europe PMC Scholia
  16. Koller KJ, Lowe DG, Bennett GL, Minamino N, Kangawa K, Matsuo H, Goeddel DV.; ''Selective activation of the B natriuretic peptide receptor by C-type natriuretic peptide (CNP).''; PubMed Europe PMC Scholia
  17. Zamparelli C, Macquaide N, Colotti G, Verzili D, Seidler T, Smith GL, Chiancone E.; ''Activation of the cardiac Na(+)-Ca(2+) exchanger by sorcin via the interaction of the respective Ca(2+)-binding domains.''; PubMed Europe PMC Scholia
  18. Keryanov S, Gardner KL.; ''Physical mapping and characterization of the human Na,K-ATPase isoform, ATP1A4.''; PubMed Europe PMC Scholia
  19. Pandey KN.; ''Guanylyl cyclase/natriuretic peptide receptor-A signaling antagonizes phosphoinositide hydrolysis, Ca(2+) release, and activation of protein kinase C.''; PubMed Europe PMC Scholia
  20. Shull MM, Pugh DG, Lingrel JB.; ''Characterization of the human Na,K-ATPase alpha 2 gene and identification of intragenic restriction fragment length polymorphisms.''; PubMed Europe PMC Scholia
  21. Bartels CF, Bükülmez H, Padayatti P, Rhee DK, van Ravenswaaij-Arts C, Pauli RM, Mundlos S, Chitayat D, Shih LY, Al-Gazali LI, Kant S, Cole T, Morton J, Cormier-Daire V, Faivre L, Lees M, Kirk J, Mortier GR, Leroy J, Zabel B, Kim CA, Crow Y, Braverman NE, van den Akker F, Warman ML.; ''Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux.''; PubMed Europe PMC Scholia
  22. Goetz R, Dover K, Laezza F, Shtraizent N, Huang X, Tchetchik D, Eliseenkova AV, Xu CF, Neubert TA, Ornitz DM, Goldfarb M, Mohammadi M.; ''Crystal structure of a fibroblast growth factor homologous factor (FHF) defines a conserved surface on FHFs for binding and modulation of voltage-gated sodium channels.''; PubMed Europe PMC Scholia
  23. McDonald TV, Yu Z, Ming Z, Palma E, Meyers MB, Wang KW, Goldstein SA, Fishman GI.; ''A minK-HERG complex regulates the cardiac potassium current I(Kr).''; PubMed Europe PMC Scholia
  24. Cherniavsky Lev M, Karlish SJ, Garty H.; ''Cardiac glycosides induced toxicity in human cells expressing α1-, α2-, or α3-isoforms of Na-K-ATPase.''; PubMed Europe PMC Scholia
  25. Tunwell RE, Wickenden C, Bertrand BM, Shevchenko VI, Walsh MB, Allen PD, Lai FA.; ''The human cardiac muscle ryanodine receptor-calcium release channel: identification, primary structure and topological analysis.''; PubMed Europe PMC Scholia
  26. Lotshaw DP.; ''Biophysical, pharmacological, and functional characteristics of cloned and native mammalian two-pore domain K+ channels.''; PubMed Europe PMC Scholia
  27. Isbrandt D, Leicher T, Waldschütz R, Zhu X, Luhmann U, Michel U, Sauter K, Pongs O.; ''Gene structures and expression profiles of three human KCND (Kv4) potassium channels mediating A-type currents I(TO) and I(SA).''; PubMed Europe PMC Scholia
  28. Agostini S, Ali H, Vardabasso C, Fittipaldi A, Tasciotti E, Cereseto A, Bugatti A, Rusnati M, Lusic M, Giacca M.; ''Inhibition of Non Canonical HIV-1 Tat Secretion Through the Cellular Na+,K+-ATPase Blocks HIV-1 Infection.''; PubMed Europe PMC Scholia
  29. Mohamed TM, Oceandy D, Prehar S, Alatwi N, Hegab Z, Baudoin FM, Pickard A, Zaki AO, Nadif R, Cartwright EJ, Neyses L.; ''Specific role of neuronal nitric-oxide synthase when tethered to the plasma membrane calcium pump in regulating the beta-adrenergic signal in the myocardium.''; PubMed Europe PMC Scholia
  30. Lin YL, Chen CY, Cheng CP, Chang LS.; ''Protein-protein interactions of KChIP proteins and Kv4.2.''; PubMed Europe PMC Scholia
  31. Bokkala S, el-Daher SS, Kakkar VV, Wuytack F, Authi KS.; ''Localization and identification of Ca2+ATPases in highly purified human platelet plasma and intracellular membranes. Evidence that the monoclonal antibody PL/IM 430 recognizes the SERCA 3 Ca2+ATPase in human platelets.''; PubMed Europe PMC Scholia
  32. Glaves JP, Trieber CA, Ceholski DK, Stokes DL, Young HS.; ''Phosphorylation and mutation of phospholamban alter physical interactions with the sarcoplasmic reticulum calcium pump.''; PubMed Europe PMC Scholia
  33. Zorzato F, Fujii J, Otsu K, Phillips M, Green NM, Lai FA, Meissner G, MacLennan DH.; ''Molecular cloning of cDNA encoding human and rabbit forms of the Ca2+ release channel (ryanodine receptor) of skeletal muscle sarcoplasmic reticulum.''; PubMed Europe PMC Scholia
  34. Lee Y, Shioi T, Kasahara H, Jobe SM, Wiese RJ, Markham BE, Izumo S.; ''The cardiac tissue-restricted homeobox protein Csx/Nkx2.5 physically associates with the zinc finger protein GATA4 and cooperatively activates atrial natriuretic factor gene expression.''; PubMed Europe PMC Scholia
  35. Ono M, Yano M, Hino A, Suetomi T, Xu X, Susa T, Uchinoumi H, Tateishi H, Oda T, Okuda S, Doi M, Kobayashi S, Yamamoto T, Koseki N, Kyushiki H, Ikemoto N, Matsuzaki M.; ''Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca(2+) release in heart failure.''; PubMed Europe PMC Scholia
  36. Mahaut-Smith MP, Sage SO, Rink TJ.; ''Receptor-activated single channels in intact human platelets.''; PubMed Europe PMC Scholia
  37. Choudhury K, McQuillin A, Puri V, Pimm J, Datta S, Thirumalai S, Krasucki R, Lawrence J, Bass NJ, Quested D, Crombie C, Fraser G, Walker N, Nadeem H, Johnson S, Curtis D, St Clair D, Gurling HM.; ''A genetic association study of chromosome 11q22-24 in two different samples implicates the FXYD6 gene, encoding phosphohippolin, in susceptibility to schizophrenia.''; PubMed Europe PMC Scholia
  38. Spamer C, Heilmann C, Gerok W.; ''Ca2+-activated ATPase in microsomes from human liver.''; PubMed Europe PMC Scholia
  39. Brust PF, Simerson S, McCue AF, Deal CR, Schoonmaker S, Williams ME, Veliçelebi G, Johnson EC, Harpold MM, Ellis SB.; ''Human neuronal voltage-dependent calcium channels: studies on subunit structure and role in channel assembly.''; PubMed Europe PMC Scholia
  40. Gabellini N, Bortoluzzi S, Danieli GA, Carafoli E.; ''The human SLC8A3 gene and the tissue-specific Na+/Ca2+ exchanger 3 isoforms.''; PubMed Europe PMC Scholia
  41. Malik N, Canfield VA, Beckers MC, Gros P, Levenson R.; ''Identification of the mammalian Na,K-ATPase 3 subunit.''; PubMed Europe PMC Scholia
  42. Nakamura TY, Nandi S, Pountney DJ, Artman M, Rudy B, Coetzee WA.; ''Different effects of the Ca(2+)-binding protein, KChIP1, on two Kv4 subfamily members, Kv4.1 and Kv4.2.''; PubMed Europe PMC Scholia
  43. Komuro I, Wenninger KE, Philipson KD, Izumo S.; ''Molecular cloning and characterization of the human cardiac Na+/Ca2+ exchanger cDNA.''; PubMed Europe PMC Scholia
  44. Duan W, Zhou J, Li W, Zhou T, Chen Q, Yang F, Wei T.; ''Plasma membrane calcium ATPase 4b inhibits nitric oxide generation through calcium-induced dynamic interaction with neuronal nitric oxide synthase.''; PubMed Europe PMC Scholia
  45. Sundivakkam PC, Freichel M, Singh V, Yuan JP, Vogel SM, Flockerzi V, Malik AB, Tiruppathi C.; ''The Ca(2+) sensor stromal interaction molecule 1 (STIM1) is necessary and sufficient for the store-operated Ca(2+) entry function of transient receptor potential canonical (TRPC) 1 and 4 channels in endothelial cells.''; PubMed Europe PMC Scholia
  46. Fujii J, Willard HF, MacLennan DH.; ''Characterization and localization to human chromosome 1 of human fast-twitch skeletal muscle calsequestrin gene.''; PubMed Europe PMC Scholia
  47. Kim E, Youn B, Kemper L, Campbell C, Milting H, Varsanyi M, Kang C.; ''Characterization of human cardiac calsequestrin and its deleterious mutants.''; PubMed Europe PMC Scholia
  48. Liao X, Wang W, Chen S, Wu Q.; ''Role of glycosylation in corin zymogen activation.''; PubMed Europe PMC Scholia
  49. Grant AO.; ''Cardiac ion channels.''; PubMed Europe PMC Scholia
  50. Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR.; ''PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts.''; PubMed Europe PMC Scholia
  51. Gorski PA, Glaves JP, Vangheluwe P, Young HS.; ''Sarco(endo)plasmic reticulum calcium ATPase (SERCA) inhibition by sarcolipin is encoded in its luminal tail.''; PubMed Europe PMC Scholia
  52. Wu L, Yong SL, Fan C, Ni Y, Yoo S, Zhang T, Zhang X, Obejero-Paz CA, Rho HJ, Ke T, Szafranski P, Jones SW, Chen Q, Wang QK.; ''Identification of a new co-factor, MOG1, required for the full function of cardiac sodium channel Nav 1.5.''; PubMed Europe PMC Scholia
  53. Nakashima Y, Nishimura S, Maeda A, Barsoumian EL, Hakamata Y, Nakai J, Allen PD, Imoto K, Kita T.; ''Molecular cloning and characterization of a human brain ryanodine receptor.''; PubMed Europe PMC Scholia
  54. Schott JJ, Benson DW, Basson CT, Pease W, Silberbach GM, Moak JP, Maron BJ, Seidman CE, Seidman JG.; ''Congenital heart disease caused by mutations in the transcription factor NKX2-5.''; PubMed Europe PMC Scholia
  55. Kaliman P, Catalucci D, Lam JT, Kondo R, Gutiérrez JC, Reddy S, Palacín M, Zorzano A, Chien KR, Ruiz-Lozano P.; ''Myotonic dystrophy protein kinase phosphorylates phospholamban and regulates calcium uptake in cardiomyocyte sarcoplasmic reticulum.''; PubMed Europe PMC Scholia
  56. Kawakami K, Ohta T, Nojima H, Nagano K.; ''Primary structure of the alpha-subunit of human Na,K-ATPase deduced from cDNA sequence.''; PubMed Europe PMC Scholia
  57. Matsumoto T, Hisamatsu Y, Ohkusa T, Inoue N, Sato T, Suzuki S, Ikeda Y, Matsuzaki M.; ''Sorcin interacts with sarcoplasmic reticulum Ca(2+)-ATPase and modulates excitation-contraction coupling in the heart.''; PubMed Europe PMC Scholia
  58. Hennessey JA, Wei EQ, Pitt GS.; ''Fibroblast growth factor homologous factors modulate cardiac calcium channels.''; PubMed Europe PMC Scholia
  59. Chen L, Marquardt ML, Tester DJ, Sampson KJ, Ackerman MJ, Kass RS.; ''Mutation of an A-kinase-anchoring protein causes long-QT syndrome.''; PubMed Europe PMC Scholia
  60. Wang C, Hennessey JA, Kirkton RD, Wang C, Graham V, Puranam RS, Rosenberg PB, Bursac N, Pitt GS.; ''Fibroblast growth factor homologous factor 13 regulates Na+ channels and conduction velocity in murine hearts.''; PubMed Europe PMC Scholia
  61. Schatzmann HJ.; ''ATP-dependent Ca++-extrusion from human red cells.''; PubMed Europe PMC Scholia
  62. Swoboda KJ, Kanavakis E, Xaidara A, Johnson JE, Leppert MF, Schlesinger-Massart MB, Ptacek LJ, Silver K, Youroukos S.; ''Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation.''; PubMed Europe PMC Scholia
  63. Marfatia KA, Harreman MT, Fanara P, Vertino PM, Corbett AH.; ''Identification and characterization of the human MOG1 gene.''; PubMed Europe PMC Scholia
  64. Shin HG, Lu Z.; ''Mechanism of the voltage sensitivity of IRK1 inward-rectifier K+ channel block by the polyamine spermine.''; PubMed Europe PMC Scholia
  65. Verma AK, Filoteo AG, Stanford DR, Wieben ED, Penniston JT, Strehler EE, Fischer R, Heim R, Vogel G, Mathews S.; ''Complete primary structure of a human plasma membrane Ca2+ pump.''; PubMed Europe PMC Scholia
  66. Yuan JP, Zeng W, Huang GN, Worley PF, Muallem S.; ''STIM1 heteromultimerizes TRPC channels to determine their function as store-operated channels.''; PubMed Europe PMC Scholia
  67. Ovchinnikov YuA, Monastyrskaya GS, Broude NE, Ushkaryov YuA, Melkov AM, Smirnov YuV, Malyshev IV, Allikmets RL, Kostina MB, Dulubova IE.; ''Family of human Na+, K+-ATPase genes. Structure of the gene for the catalytic subunit (alpha III-form) and its relationship with structural features of the protein.''; PubMed Europe PMC Scholia
  68. Bush EW, Helmke SM, Birnbaum RA, Perryman MB.; ''Myotonic dystrophy protein kinase domains mediate localization, oligomerization, novel catalytic activity, and autoinhibition.''; PubMed Europe PMC Scholia
  69. Ong HL, Cheng KT, Liu X, Bandyopadhyay BC, Paria BC, Soboloff J, Pani B, Gwack Y, Srikanth S, Singh BB, Gill DL, Ambudkar IS.; ''Dynamic assembly of TRPC1-STIM1-Orai1 ternary complex is involved in store-operated calcium influx. Evidence for similarities in store-operated and calcium release-activated calcium channel components.''; PubMed Europe PMC Scholia
  70. Smith TW.; ''The basic mechanism of inotropic action of digitalis glycosides.''; PubMed Europe PMC Scholia
  71. Lane LK, Shull MM, Whitmer KR, Lingrel JB.; ''Characterization of two genes for the human Na,K-ATPase beta subunit.''; PubMed Europe PMC Scholia
  72. Dulhunty AF, Pouliquin P, Coggan M, Gage PW, Board PG.; ''A recently identified member of the glutathione transferase structural family modifies cardiac RyR2 substate activity, coupled gating and activation by Ca2+ and ATP.''; PubMed Europe PMC Scholia
  73. Yan W, Wu F, Morser J, Wu Q.; ''Corin, a transmembrane cardiac serine protease, acts as a pro-atrial natriuretic peptide-converting enzyme.''; PubMed Europe PMC Scholia
  74. Vanmolkot KR, Kors EE, Hottenga JJ, Terwindt GM, Haan J, Hoefnagels WA, Black DF, Sandkuijl LA, Frants RR, Ferrari MD, van den Maagdenberg AM.; ''Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions.''; PubMed Europe PMC Scholia
  75. Board PG, Coggan M, Watson S, Gage PW, Dulhunty AF.; ''CLIC-2 modulates cardiac ryanodine receptor Ca2+ release channels.''; PubMed Europe PMC Scholia
  76. Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, Goldstein SA.; ''MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia.''; PubMed Europe PMC Scholia
  77. Mittmann K, Jaquet K, Heilmeyer LM.; ''A common motif of two adjacent phosphoserines in bovine, rabbit and human cardiac troponin I.''; PubMed Europe PMC Scholia
  78. Enyedi P, Czirják G.; ''Molecular background of leak K+ currents: two-pore domain potassium channels.''; PubMed Europe PMC Scholia
  79. An WF, Bowlby MR, Betty M, Cao J, Ling HP, Mendoza G, Hinson JW, Mattsson KI, Strassle BW, Trimmer JS, Rhodes KJ.; ''Modulation of A-type potassium channels by a family of calcium sensors.''; PubMed Europe PMC Scholia
  80. Ceholski DK, Trieber CA, Holmes CF, Young HS.; ''Lethal, hereditary mutants of phospholamban elude phosphorylation by protein kinase A.''; PubMed Europe PMC Scholia
  81. Goldstein SA, Bayliss DA, Kim D, Lesage F, Plant LD, Rajan S.; ''International Union of Pharmacology. LV. Nomenclature and molecular relationships of two-P potassium channels.''; PubMed Europe PMC Scholia
  82. Smith JS, Rousseau E, Meissner G.; ''Calmodulin modulation of single sarcoplasmic reticulum Ca2+-release channels from cardiac and skeletal muscle.''; PubMed Europe PMC Scholia
  83. Franceschini S, Ilari A, Verzili D, Zamparelli C, Antaramian A, Rueda A, Valdivia HH, Chiancone E, Colotti G.; ''Molecular basis for the impaired function of the natural F112L sorcin mutant: X-ray crystal structure, calcium affinity, and interaction with annexin VII and the ryanodine receptor.''; PubMed Europe PMC Scholia
  84. Li Z, Matsuoka S, Hryshko LV, Nicoll DA, Bersohn MM, Burke EP, Lifton RP, Philipson KD.; ''Cloning of the NCX2 isoform of the plasma membrane Na(+)-Ca2+ exchanger.''; PubMed Europe PMC Scholia
  85. Yang L, Katchman A, Morrow JP, Doshi D, Marx SO.; ''Cardiac L-type calcium channel (Cav1.2) associates with gamma subunits.''; PubMed Europe PMC Scholia
  86. Meij IC, Koenderink JB, van Bokhoven H, Assink KF, Groenestege WT, de Pont JJ, Bindels RJ, Monnens LA, van den Heuvel LP, Knoers NV.; ''Dominant isolated renal magnesium loss is caused by misrouting of the Na(+),K(+)-ATPase gamma-subunit.''; PubMed Europe PMC Scholia
  87. Gellens ME, George AL, Chen LQ, Chahine M, Horn R, Barchi RL, Kallen RG.; ''Primary structure and functional expression of the human cardiac tetrodotoxin-insensitive voltage-dependent sodium channel.''; PubMed Europe PMC Scholia
  88. de Carvalho Aguiar P, Sweadner KJ, Penniston JT, Zaremba J, Liu L, Caton M, Linazasoro G, Borg M, Tijssen MA, Bressman SB, Dobyns WB, Brashear A, Ozelius LJ.; ''Mutations in the Na+/K+ -ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism.''; PubMed Europe PMC Scholia
  89. Hauck C, Potter T, Bartz M, Wittwer T, Wahlers T, Mehlhorn U, Scheiner-Bobis G, McDonough AA, Bloch W, Schwinger RH, Müller-Ehmsen J.; ''Isoform specificity of cardiac glycosides binding to human Na+,K+-ATPase alpha1beta1, alpha2beta1 and alpha3beta1.''; PubMed Europe PMC Scholia
  90. Katz A, Lifshitz Y, Bab-Dinitz E, Kapri-Pardes E, Goldshleger R, Tal DM, Karlish SJ.; ''Selectivity of digitalis glycosides for isoforms of human Na,K-ATPase.''; PubMed Europe PMC Scholia
  91. Ruiz A, Bhat SP, Bok D.; ''Expression and synthesis of the Na,K-ATPase beta 2 subunit in human retinal pigment epithelium.''; PubMed Europe PMC Scholia
  92. Huang GN, Zeng W, Kim JY, Yuan JP, Han L, Muallem S, Worley PF.; ''STIM1 carboxyl-terminus activates native SOC, I(crac) and TRPC1 channels.''; PubMed Europe PMC Scholia
  93. Zhang R, Epstein HF.; ''Homodimerization through coiled-coil regions enhances activity of the myotonic dystrophy protein kinase.''; PubMed Europe PMC Scholia
  94. Zeng W, Yuan JP, Kim MS, Choi YJ, Huang GN, Worley PF, Muallem S.; ''STIM1 gates TRPC channels, but not Orai1, by electrostatic interaction.''; PubMed Europe PMC Scholia
  95. Bartos DC, Grandi E, Ripplinger CM.; ''Ion Channels in the Heart.''; PubMed Europe PMC Scholia
  96. Cheng KT, Liu X, Ong HL, Swaim W, Ambudkar IS.; ''Local Ca²+ entry via Orai1 regulates plasma membrane recruitment of TRPC1 and controls cytosolic Ca²+ signals required for specific cell functions.''; PubMed Europe PMC Scholia
  97. Makielski JC, Ye B, Valdivia CR, Pagel MD, Pu J, Tester DJ, Ackerman MJ.; ''A ubiquitous splice variant and a common polymorphism affect heterologous expression of recombinant human SCN5A heart sodium channels.''; PubMed Europe PMC Scholia
  98. Murakami M, Nakagawa M, Olson EN, Nakagawa O.; ''A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome.''; PubMed Europe PMC Scholia
  99. Toyofuku T, Curotto Kurzydlowski K, Narayanan N, MacLennan DH.; ''Identification of Ser38 as the site in cardiac sarcoplasmic reticulum Ca(2+)-ATPase that is phosphorylated by Ca2+/calmodulin-dependent protein kinase.''; PubMed Europe PMC Scholia
  100. Pioletti M, Findeisen F, Hura GL, Minor DL.; ''Three-dimensional structure of the KChIP1-Kv4.3 T1 complex reveals a cross-shaped octamer.''; PubMed Europe PMC Scholia
  101. Wang H, Yan Y, Liu Q, Huang Y, Shen Y, Chen L, Chen Y, Yang Q, Hao Q, Wang K, Chai J.; ''Structural basis for modulation of Kv4 K+ channels by auxiliary KChIP subunits.''; PubMed Europe PMC Scholia
  102. Park DS, Fishman GI.; ''The cardiac conduction system.''; PubMed Europe PMC Scholia
  103. Plant LD, Xiong D, Dai H, Goldstein SA.; ''Individual IKs channels at the surface of mammalian cells contain two KCNE1 accessory subunits.''; PubMed Europe PMC Scholia
  104. Lu QW, Wu XY, Morimoto S.; ''Inherited cardiomyopathies caused by troponin mutations.''; PubMed Europe PMC Scholia
  105. Wang C, Wang C, Hoch EG, Pitt GS.; ''Identification of novel interaction sites that determine specificity between fibroblast growth factor homologous factors and voltage-gated sodium channels.''; PubMed Europe PMC Scholia
  106. Zhang P, Kirk JA, Ji W, dos Remedios CG, Kass DA, Van Eyk JE, Murphy AM.; ''Multiple reaction monitoring to identify site-specific troponin I phosphorylated residues in the failing human heart.''; PubMed Europe PMC Scholia
  107. Benson DW, Silberbach GM, Kavanaugh-McHugh A, Cottrill C, Zhang Y, Riggs S, Smalls O, Johnson MC, Watson MS, Seidman JG, Seidman CE, Plowden J, Kugler JD.; ''Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
114892view16:40, 25 January 2021ReactomeTeamReactome version 75
113338view11:41, 2 November 2020ReactomeTeamReactome version 74
112549view15:51, 9 October 2020ReactomeTeamReactome version 73
101463view11:33, 1 November 2018ReactomeTeamreactome version 66
101001view21:12, 31 October 2018ReactomeTeamreactome version 65
100537view19:46, 31 October 2018ReactomeTeamreactome version 64
100084view16:30, 31 October 2018ReactomeTeamreactome version 63
99635view15:02, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93831view13:39, 16 August 2017ReactomeTeamreactome version 61
93384view11:22, 9 August 2017ReactomeTeamreactome version 61
87432view13:30, 22 July 2016MkutmonOntology Term : 'regulatory pathway' added !
86470view09:19, 11 July 2016ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ABCC9 ProteinO60706 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
AHCYL1 ProteinO43865 (Uniprot-TrEMBL)
AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerComplexR-HSA-5226920 (Reactome)
AHCYL1:NAD+ComplexR-HSA-5226942 (Reactome)
AKAP9 ProteinQ99996 (Uniprot-TrEMBL)
AKAP9:KCNQ1 tetramer:KCNE dimerComplexR-HSA-5577100 (Reactome)
ASPH ProteinQ12797 (Uniprot-TrEMBL)
ATP1A1 ProteinP05023 (Uniprot-TrEMBL)
ATP1A2 ProteinP50993 (Uniprot-TrEMBL)
ATP1A3 ProteinP13637 (Uniprot-TrEMBL)
ATP1A4 ProteinQ13733 (Uniprot-TrEMBL)
ATP1A:ATP1B:FXYDComplexR-HSA-936770 (Reactome)
ATP1B1 ProteinP05026 (Uniprot-TrEMBL)
ATP1B2 ProteinP14415 (Uniprot-TrEMBL)
ATP1B3 ProteinP54709 (Uniprot-TrEMBL)
ATP2A1 ProteinO14983 (Uniprot-TrEMBL)
ATP2A1-3ComplexR-HSA-418312 (Reactome)
ATP2A2 ProteinP16615 (Uniprot-TrEMBL)
ATP2A3 ProteinQ93084 (Uniprot-TrEMBL)
ATP2B1 ProteinP20020 (Uniprot-TrEMBL)
ATP2B1-4ComplexR-HSA-418306 (Reactome)
ATP2B2 ProteinQ01814 (Uniprot-TrEMBL)
ATP2B3 ProteinQ16720 (Uniprot-TrEMBL)
ATP2B4 ProteinP23634 (Uniprot-TrEMBL)
ATP2B4:NOS1ComplexR-HSA-5617181 (Reactome)
ATP2B4ProteinP23634 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
CACNA1C ProteinQ13936 (Uniprot-TrEMBL)
CACNA1D ProteinQ01668 (Uniprot-TrEMBL)
CACNA1F ProteinO60840 (Uniprot-TrEMBL)
CACNA1S ProteinQ13698 (Uniprot-TrEMBL)
CACNA2D1(25-956) ProteinQ9UIU0 (Uniprot-TrEMBL)
CACNA2D1(957-1103) ProteinP54289 (Uniprot-TrEMBL)
CACNA2D2(1002-1150) ProteinQ9NY47 (Uniprot-TrEMBL)
CACNA2D2(19-1001) ProteinQ9NY47 (Uniprot-TrEMBL)
CACNA2D3(29-?) ProteinQ8IZS8 (Uniprot-TrEMBL)
CACNA2D3(?-1091) ProteinQ8IZS8 (Uniprot-TrEMBL)
CACNA2D4(20-991) ProteinQ7Z3S7 (Uniprot-TrEMBL)
CACNA2D4(992-1137) ProteinQ7Z3S7 (Uniprot-TrEMBL)
CACNB1 ProteinQ02641 (Uniprot-TrEMBL)
CACNB2 ProteinQ08289 (Uniprot-TrEMBL)
CACNB3 ProteinP54284 (Uniprot-TrEMBL)
CACNB4 ProteinO00305 (Uniprot-TrEMBL)
CACNG1 ProteinQ06432 (Uniprot-TrEMBL)
CACNG2 ProteinQ9Y698 (Uniprot-TrEMBL)
CACNG3 ProteinO60359 (Uniprot-TrEMBL)
CACNG4 ProteinQ9UBN1 (Uniprot-TrEMBL)
CACNG5 ProteinQ9UF02 (Uniprot-TrEMBL)
CACNG6 ProteinQ9BXT2 (Uniprot-TrEMBL)
CACNG7 ProteinP62955 (Uniprot-TrEMBL)
CACNG8 ProteinQ8WXS5 (Uniprot-TrEMBL)
CALM1 ProteinP0DP23 (Uniprot-TrEMBL)
CALM1ProteinP0DP23 (Uniprot-TrEMBL)
CAMK2 heteromer:CALM:4xCa2+ComplexR-HSA-444601 (Reactome)
CASQ1 polymer R-HSA-2855198 (Reactome)
CASQ2 polymer R-HSA-2855188 (Reactome)
CLIC2ProteinO15247 (Uniprot-TrEMBL)
CORIN(802-1042)ProteinQ9Y5Q5 (Uniprot-TrEMBL)
CRAC channelComplexR-HSA-434679 (Reactome)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
DMPK ProteinQ09013 (Uniprot-TrEMBL)
DMPK dimerComplexR-HSA-5578802 (Reactome)
FGF11 ProteinQ92914 (Uniprot-TrEMBL)
FGF11-14ComplexR-HSA-5578833 (Reactome)
FGF12 ProteinP61328 (Uniprot-TrEMBL)
FGF13 ProteinQ92913 (Uniprot-TrEMBL)
FGF14 ProteinQ92915 (Uniprot-TrEMBL)
FKBP1B ProteinP68106 (Uniprot-TrEMBL)
FXYD1 ProteinO00168 (Uniprot-TrEMBL)
FXYD2 ProteinP54710 (Uniprot-TrEMBL)
FXYD3 ProteinQ14802 (Uniprot-TrEMBL)
FXYD4 ProteinP59646 (Uniprot-TrEMBL)
FXYD6 ProteinQ9H0Q3 (Uniprot-TrEMBL)
FXYD7 ProteinP58549 (Uniprot-TrEMBL)
GATA4 ProteinP43694 (Uniprot-TrEMBL)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HIPK1 ProteinQ86Z02 (Uniprot-TrEMBL)
HIPK2 ProteinQ9H2X6 (Uniprot-TrEMBL)
I(1,4,5)P3 MetaboliteCHEBI:16595 (ChEBI)
I(1,4,5)P3MetaboliteCHEBI:16595 (ChEBI)
IP3R tetramer:I(1,4,5)P3:4xCa2+ComplexR-HSA-139839 (Reactome)
ITPR1 ProteinQ14643 (Uniprot-TrEMBL)
ITPR2 ProteinQ14571 (Uniprot-TrEMBL)
ITPR3 ProteinQ14573 (Uniprot-TrEMBL)
ITPR:I(1,4,5)P3 tetramerComplexR-HSA-169696 (Reactome)
K+MetaboliteCHEBI:29103 (ChEBI)
KAT2B ProteinQ92831 (Uniprot-TrEMBL)
KCND tetramer:KCNIP tetramerComplexR-HSA-5577126 (Reactome)
KCND1 ProteinQ9NSA2 (Uniprot-TrEMBL)
KCND2 ProteinQ9NZV8 (Uniprot-TrEMBL)
KCND3 ProteinQ9UK17 (Uniprot-TrEMBL)
KCNE1 ProteinP15382 (Uniprot-TrEMBL)
KCNE1L ProteinQ9UJ90 (Uniprot-TrEMBL)
KCNE2 ProteinQ9Y6J6 (Uniprot-TrEMBL)
KCNE3 ProteinQ9Y6H6 (Uniprot-TrEMBL)
KCNE4 ProteinQ8WWG9 (Uniprot-TrEMBL)
KCNH2 ProteinQ12809 (Uniprot-TrEMBL)
KCNH2:KCNEComplexR-HSA-5577121 (Reactome)
KCNIP1 ProteinQ9NZI2 (Uniprot-TrEMBL)
KCNIP2 ProteinQ9NS61 (Uniprot-TrEMBL)
KCNIP3 ProteinQ9Y2W7 (Uniprot-TrEMBL)
KCNIP4 ProteinQ6PIL6 (Uniprot-TrEMBL)
KCNJ tetramerComplexR-HSA-1299200 (Reactome) Kir 2 channels form heterotetramers of any two of the four subunits.
KCNJ11 ProteinQ14654 (Uniprot-TrEMBL)
KCNJ11:ABCC9ComplexR-HSA-5678267 (Reactome)
KCNJ12 ProteinQ14500 (Uniprot-TrEMBL)
KCNJ14 ProteinQ9UNX9 (Uniprot-TrEMBL)
KCNJ2 ProteinP63252 (Uniprot-TrEMBL)
KCNJ4 ProteinP48050 (Uniprot-TrEMBL)
KCNK dimersComplexR-HSA-5578913 (Reactome)
KCNK1 ProteinO00180 (Uniprot-TrEMBL)
KCNK10 ProteinP57789 (Uniprot-TrEMBL)
KCNK12 ProteinQ9HB15 (Uniprot-TrEMBL)
KCNK13 ProteinQ9HB14 (Uniprot-TrEMBL)
KCNK15 ProteinQ9H427 (Uniprot-TrEMBL)
KCNK16 ProteinQ96T55 (Uniprot-TrEMBL)
KCNK17 ProteinQ96T54 (Uniprot-TrEMBL)
KCNK18 ProteinQ7Z418 (Uniprot-TrEMBL)
KCNK2 ProteinO95069 (Uniprot-TrEMBL)
KCNK3 ProteinO14649 (Uniprot-TrEMBL)
KCNK4 ProteinQ9NYG8 (Uniprot-TrEMBL)
KCNK5 ProteinO95279 (Uniprot-TrEMBL)
KCNK6 ProteinQ9Y257 (Uniprot-TrEMBL)
KCNK7 ProteinQ9Y2U2 (Uniprot-TrEMBL)
KCNK9 ProteinQ9NPC2 (Uniprot-TrEMBL)
KCNQ1 ProteinP51787 (Uniprot-TrEMBL)
LTCC heteropentamer (closed)ComplexR-HSA-5577115 (Reactome)
LTCC heteropentamer (open)ComplexR-HSA-5577111 (Reactome)
NAD+ MetaboliteCHEBI:15846 (ChEBI)
NKX2-5 ProteinP52952 (Uniprot-TrEMBL)
NKX2-5:GATA4:HIPK1,2ComplexR-HSA-5578875 (Reactome)
NOS1 ProteinP29475 (Uniprot-TrEMBL)
NOS1ProteinP29475 (Uniprot-TrEMBL)
NPPA geneGeneProductENSG00000175206 (Ensembl)
NPPA(1-153)ProteinP01160 (Uniprot-TrEMBL)
NPPA(1-25)ProteinP01160 (Uniprot-TrEMBL)
NPPA(124-151) ProteinP01160 (Uniprot-TrEMBL)
NPPA(124-151):NPR1 dimerComplexR-HSA-6784597 (Reactome)
NPPA(124-151)ProteinP01160 (Uniprot-TrEMBL)
NPPA(26-55)ProteinP01160 (Uniprot-TrEMBL)
NPPA(56-123)ProteinP01160 (Uniprot-TrEMBL)
NPPC ProteinP23582 (Uniprot-TrEMBL)
NPPCProteinP23582 (Uniprot-TrEMBL)
NPR1 ProteinP16066 (Uniprot-TrEMBL)
NPR1 dimerComplexR-HSA-6784600 (Reactome)
NPR2 ProteinP20594 (Uniprot-TrEMBL)
NPR2:NPPCComplexR-HSA-5692430 (Reactome)
NPR2ProteinP20594 (Uniprot-TrEMBL)
Na+MetaboliteCHEBI:29101 (ChEBI)
ORAI1 ProteinQ96D31 (Uniprot-TrEMBL)
ORAI2 ProteinQ96SN7 (Uniprot-TrEMBL)
PLN ProteinP26678 (Uniprot-TrEMBL)
PLN pentamerComplexR-HSA-5578811 (Reactome)
PRKACAProteinP17612 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
RANGRFProteinQ9HD47 (Uniprot-TrEMBL)
RYR

tetramer:FKBP1B tetramer:CASQ

polymer:TRDN:junctin
ComplexR-HSA-2855167 (Reactome)
RYR1 ProteinP21817 (Uniprot-TrEMBL)
RYR2 ProteinQ92736 (Uniprot-TrEMBL)
RYR3 ProteinQ15413 (Uniprot-TrEMBL)
SCN10A ProteinQ9Y5Y9 (Uniprot-TrEMBL)
SCN11A ProteinQ9UI33 (Uniprot-TrEMBL)
SCN1A ProteinP35498 (Uniprot-TrEMBL)
SCN1B ProteinQ07699 (Uniprot-TrEMBL)
SCN2A ProteinQ99250 (Uniprot-TrEMBL)
SCN2B ProteinO60939 (Uniprot-TrEMBL)
SCN3A ProteinQ9NY46 (Uniprot-TrEMBL)
SCN3B ProteinQ9NY72 (Uniprot-TrEMBL)
SCN4A ProteinP35499 (Uniprot-TrEMBL)
SCN4B ProteinQ8IWT1 (Uniprot-TrEMBL)
SCN5A ProteinQ14524 (Uniprot-TrEMBL)
SCN7A ProteinQ01118 (Uniprot-TrEMBL)
SCN8A ProteinQ9UQD0 (Uniprot-TrEMBL)
SCN9A ProteinQ15858 (Uniprot-TrEMBL)
SCNAs:SCNBsComplexR-HSA-443632 (Reactome) Sodium-channel proteins in the mammalian brain are composed of a complex of a 260 kDa alpha subunit in association with one or more auxiliary beta subunits (beta1, beta2 and/or beta3). Nine alpha subunits (Nav1.1-Nav1.9) have been functionally characterized, and a tenth related isoform (Nax) may also function as a Na+ channel.
SLC8A1 ProteinP32418 (Uniprot-TrEMBL)
SLC8A1,2,3ComplexR-HSA-425675 (Reactome)
SLC8A2 ProteinQ9UPR5 (Uniprot-TrEMBL)
SLC8A3 ProteinP57103 (Uniprot-TrEMBL)
SLNProteinO00631 (Uniprot-TrEMBL)
SRIProteinP30626 (Uniprot-TrEMBL)
STIM1 ProteinQ13586 (Uniprot-TrEMBL)
STIM1:TRPC1ComplexR-HSA-2089954 (Reactome)
TBX5 ProteinQ99593 (Uniprot-TrEMBL)
TBX5:WWTR1:PCAFComplexR-HSA-2032799 (Reactome)
TNNI3ProteinP19429 (Uniprot-TrEMBL)
TRDN ProteinQ13061 (Uniprot-TrEMBL)
TRPC1 ProteinP48995 (Uniprot-TrEMBL)
WWTR1 ProteinQ9GZV5 (Uniprot-TrEMBL)
p-S16-PLN ProteinP26678 (Uniprot-TrEMBL)
p-S16-PLN pentamerComplexR-HSA-5578810 (Reactome)
p-S23,S24-TNNI3ProteinP19429 (Uniprot-TrEMBL)
p-T286-CAMK2A ProteinQ9UQM7 (Uniprot-TrEMBL)
p-T287-CAMK2B ProteinQ13554 (Uniprot-TrEMBL)
p-T287-CAMK2D ProteinQ13557 (Uniprot-TrEMBL)
p-T287-CAMK2G ProteinQ13555 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-5578777 (Reactome)
ADPArrowR-HSA-5617179 (Reactome)
ADPArrowR-HSA-5617182 (Reactome)
ADPArrowR-HSA-936897 (Reactome)
AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerArrowR-HSA-5226904 (Reactome)
AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerTBarR-HSA-169683 (Reactome)
AHCYL1:NAD+R-HSA-5226904 (Reactome)
AKAP9:KCNQ1 tetramer:KCNE dimermim-catalysisR-HSA-5577050 (Reactome)
ATP1A:ATP1B:FXYDmim-catalysisR-HSA-936897 (Reactome)
ATP2A1-3mim-catalysisR-HSA-427910 (Reactome)
ATP2B1-4mim-catalysisR-HSA-418309 (Reactome)
ATP2B4:NOS1ArrowR-HSA-5617178 (Reactome)
ATP2B4:NOS1ArrowR-HSA-5617179 (Reactome)
ATP2B4:NOS1ArrowR-HSA-5617182 (Reactome)
ATP2B4R-HSA-5617178 (Reactome)
ATPArrowR-HSA-2855020 (Reactome)
ATPR-HSA-5578777 (Reactome)
ATPR-HSA-5617179 (Reactome)
ATPR-HSA-5617182 (Reactome)
ATPR-HSA-936897 (Reactome)
ArrowR-HSA-427910 (Reactome)
CALM1TBarR-HSA-425661 (Reactome)
CAMK2 heteromer:CALM:4xCa2+ArrowR-HSA-427910 (Reactome)
CAMK2 heteromer:CALM:4xCa2+TBarR-HSA-5576895 (Reactome)
CLIC2TBarR-HSA-2855020 (Reactome)
CORIN(802-1042)mim-catalysisR-HSA-5578783 (Reactome)
CRAC channelmim-catalysisR-HSA-434798 (Reactome)
Ca2+ArrowR-HSA-139854 (Reactome)
Ca2+ArrowR-HSA-169683 (Reactome)
Ca2+ArrowR-HSA-2089943 (Reactome)
Ca2+ArrowR-HSA-2855020 (Reactome)
Ca2+ArrowR-HSA-418309 (Reactome)
Ca2+ArrowR-HSA-425661 (Reactome)
Ca2+ArrowR-HSA-427910 (Reactome)
Ca2+ArrowR-HSA-434798 (Reactome)
Ca2+ArrowR-HSA-5577213 (Reactome)
Ca2+R-HSA-139854 (Reactome)
Ca2+R-HSA-169683 (Reactome)
Ca2+R-HSA-2089943 (Reactome)
Ca2+R-HSA-2855020 (Reactome)
Ca2+R-HSA-418309 (Reactome)
Ca2+R-HSA-425661 (Reactome)
Ca2+R-HSA-427910 (Reactome)
Ca2+R-HSA-434798 (Reactome)
Ca2+R-HSA-5577213 (Reactome)
DMPK dimermim-catalysisR-HSA-5578777 (Reactome)
FGF11-14ArrowR-HSA-5576895 (Reactome)
H+ArrowR-HSA-427910 (Reactome)
H+R-HSA-427910 (Reactome)
H2OR-HSA-936897 (Reactome)
I(1,4,5)P3ArrowR-HSA-169683 (Reactome)
IP3R tetramer:I(1,4,5)P3:4xCa2+mim-catalysisR-HSA-139854 (Reactome)
ITPR:I(1,4,5)P3 tetramerR-HSA-5226904 (Reactome)
ITPR:I(1,4,5)P3 tetramermim-catalysisR-HSA-169683 (Reactome)
K+ArrowR-HSA-1296046 (Reactome)
K+ArrowR-HSA-5577050 (Reactome)
K+ArrowR-HSA-5577234 (Reactome)
K+ArrowR-HSA-5577237 (Reactome)
K+ArrowR-HSA-5578910 (Reactome)
K+ArrowR-HSA-5678261 (Reactome)
K+ArrowR-HSA-936897 (Reactome)
K+R-HSA-1296046 (Reactome)
K+R-HSA-5577050 (Reactome)
K+R-HSA-5577234 (Reactome)
K+R-HSA-5577237 (Reactome)
K+R-HSA-5578910 (Reactome)
K+R-HSA-5678261 (Reactome)
K+R-HSA-936897 (Reactome)
KCND tetramer:KCNIP tetramermim-catalysisR-HSA-5577234 (Reactome)
KCNH2:KCNEmim-catalysisR-HSA-5577237 (Reactome)
KCNJ tetramermim-catalysisR-HSA-1296046 (Reactome)
KCNJ11:ABCC9mim-catalysisR-HSA-5678261 (Reactome)
KCNK dimersmim-catalysisR-HSA-5578910 (Reactome)
LTCC heteropentamer (closed)TBarR-HSA-5577213 (Reactome)
LTCC heteropentamer (open)mim-catalysisR-HSA-5577213 (Reactome)
NKX2-5:GATA4:HIPK1,2ArrowR-HSA-2032800 (Reactome)
NOS1R-HSA-5617178 (Reactome)
NPPA geneR-HSA-2032800 (Reactome)
NPPA(1-153)ArrowR-HSA-2032800 (Reactome)
NPPA(1-153)R-HSA-5578783 (Reactome)
NPPA(1-25)ArrowR-HSA-5578783 (Reactome)
NPPA(124-151):NPR1 dimerArrowR-HSA-6784598 (Reactome)
NPPA(124-151)ArrowR-HSA-5578783 (Reactome)
NPPA(124-151)R-HSA-6784598 (Reactome)
NPPA(26-55)ArrowR-HSA-5578783 (Reactome)
NPPA(56-123)ArrowR-HSA-5578783 (Reactome)
NPPCR-HSA-5692408 (Reactome)
NPR1 dimerR-HSA-6784598 (Reactome)
NPR2:NPPCArrowR-HSA-5692408 (Reactome)
NPR2R-HSA-5692408 (Reactome)
Na+ArrowR-HSA-425661 (Reactome)
Na+ArrowR-HSA-5576895 (Reactome)
Na+ArrowR-HSA-936897 (Reactome)
Na+R-HSA-425661 (Reactome)
Na+R-HSA-5576895 (Reactome)
Na+R-HSA-936897 (Reactome)
PLN pentamerR-HSA-5578777 (Reactome)
PLN pentamerR-HSA-5617182 (Reactome)
PLN pentamerTBarR-HSA-427910 (Reactome)
PRKACAmim-catalysisR-HSA-5617179 (Reactome)
PRKACAmim-catalysisR-HSA-5617182 (Reactome)
PiArrowR-HSA-936897 (Reactome)
R-HSA-1296046 (Reactome) Activation of classical Kir (K+ inwardly rectifying) channels (KCNJ2, 4, 12 and 14) results in K+ influx which contributes to the maintenance of the membrane potential (Phase 4 of the action potential). The current created by this flow of K+ is called the inward rectifying current (IK1). A channel that is inwardly-rectifying is one that passes current more easily into the cell than out of the cell. At membrane potentials negative to potassium's reversal potential, KCNJs support the flow of K+ ions into the cell, pushing the membrane potential back to the resting potential. Two factors regulate K+ permeability - cell permeability to K+ is increased at more negative membrane potentials and increasing extracellular K+ concentrations.

When the membrane potential is positive to the channel's resting potential (such as in Phase 3 of the action potential), these channels pass very little charge out of the cell. This may be due to the channel's pores being blocked by internal Mg2+ and endogenous polyamines such as spermine (Shin & Lu 2005).

Inwardly rectifying (Kir) channels contribute to potassium leak, stabilizing cells near the equilibrium reversal potential of potassium (EK). Kir channels pass small outward currents because of pore blockade by internal magnesium and polyamines; at potentials negative to EK, large inward currents are passed upon relief from blockade.
R-HSA-139854 (Reactome) The IP3 receptor (IP3R) is an intracellular calcium release channel that mobilizes Ca2+ from internal stores in the ER to the cytoplasm. Though its activity is stimulated by IP3, the principal activator of the IP3R is Ca2+. This process of calcium-induced calcium release is central to the mechanism of Ca2+ signalling. The effect of cytosolic Ca2+ on IP3R is complex: it can be both stimulatory and inhibitory and can the effect varies between IP3R isoforms. In general, the IP3Rs have a bell-shaped Ca2+ dependence when treated with low concentrations of IP3; low concentrations of Ca2+ (100–300 nM) are stimulatory but above 300 nM, Ca2+ becomes inhibitory and switches the channel off. The stimulatory effect of IP3 is to relieve Ca2+ inhibition of the channel, enabling Ca2+ activation sites to gate it.
Functionally the IP3 receptor is believed to be tetrameric, with results indicating that the tetramer is composed of 2 pairs of protein isoforms.
R-HSA-169683 (Reactome) IP3 promotes the release of intracellular calcium.
R-HSA-2032800 (Reactome) Transcription of the NPPA (ANF) gene is stimulated by the action of a transcription factor complex that includes WWTR1 (TAZ), TBX5, and the PCAF (KAT2B) histone acetyltransferase (Murakami et al. 2005). Homeobox protein NKX-2.5 (NKX2-5), in cooperation with transcription factor GATA-4 (GATA4) and interacting partners homeodomain-interacting protein kinase 1 and 2 (HIPK1 and 2), acts as a transcriptional activator factor of NPPA in mice (Lee et al. 1998). Defects in NKX2-5 can cause diverse cardiac developmental disorders (Schott et al. 1998, Benson et al. 1999).
R-HSA-2089943 (Reactome) TRPC1 forms a channel that transports Ca2+ across the plasma membrane. TRPC1 is gated by STIM1 (Ong et al. 2007).
R-HSA-2855020 (Reactome) Ryanodine receptors (RYRs) are located in the sarcoplasmic reticulum (SR) membrane and mediate the release of Ca2+ from intracellular stores during excitation-contraction (EC) coupling in both cardiac and skeletal muscle. RYRs are the largest known ion channels (>2MDa) and are functional in their homotetrameric forms. There are three mammalian isoforms (RYR1-3); RYR1 is prominent in skeletal muscle (Zorzato et al. 1990), RYR2 in cardiac muscle (Tunwell et al. 1996) and RYR3 is found in the brain (Nakashima et al. 1997, Lanner et al. 2010). The function of RYRs are controlled by peptidyl-prolyl cis-trans isomerase (FKBP1B), intracellular Ca2+-binding proteins calsequestrin 1 and 2 (CASQ1 and 2) and the anchoring proteins triadin (TRDN) and junctin. Together, they make up the Ca2+-release complex. CASQ1 and 2 buffer intra-SR Ca2+ stores in skeletal muscle and cardiac muscle respectively (Fujii et al. 1990, Kim et al. 2007). When Ca2+ concentrations reach 1mM, CASQs polymerise (Kim et al. 2007) and can attach to one end of RYRs, mediated by anchoring proteins TRDN and junctin (Taske et al. 1995). By sequestering Ca2+ ions, CASQs can inhibit RYRs function (Beard et al. 2004, Beard et al. 2009a, Beard et al. 2009b).

A member of the intracellular Cl- channel protein family, CLIC2, has also been determined to inhibit RYR-mediated Ca2+ transport (Board et al. 2004), potentially playing a role in the homeostasis of Ca2+ release from intracellular stores. Inhibition is thought to be via reducing activation of the channels by their primary endogenous cytoplasmic ligands, ATP and Ca2+ (Dulhunty et al. 2005). Protein kinase A (PKA) phosphorylation of RYR2 dissociates FKBP1B and results in defective channel function (Marx et al. 2000). The penta-EF hand protein sorcin (SRI) can modulate Ca2+-induced calcium-release in the heart via the interaction with several Ca2+ channels such as RYRs. A natural ligand, F112L, impairs this modulating activity (Franceschini et al. 2008). Calmodulin (CALM1) is considered a gatekeeper of RYR2. CALM1 acts directly by binding to RYR2 at residues 3583–3603, inhibiting RYR2 both at physiological and higher, pathological Ca2+ concentrations (Smith et al. 1989, Ono et al. 2010).
R-HSA-418309 (Reactome) The plasma membrane Ca-ATPases 1-4 (ATP2B1-4, PMCAs) are P-type Ca2+-ATPases regulated by calmodulin. The PMCA also counter-transports a proton. PMCA is important for Ca2+ homeostasis and function.
R-HSA-425661 (Reactome) The sodium/calcium exchangers 1, 2 and 3 (SCL8A1,2,3 aka NCX1,2,3) belong to one of three families that control Ca2+ flux across the plasma membrane or intracellular compartments. They extrude Ca2+ from the cell, using the electrochemical gradient of Na+ as it flows into the cell. One Ca2+ is exchanged for three Na+. During this electrogenic exchange, the membrane potential is altered. SLC8A1, 2, 3 play a minor role during phase 2, since they begin to restore ion concentrations. The high concentration of intracellular calcium starts contraction of those cells, which is sustained in the plateau phase. SLC8A1 has a ubiquitous expression profile (highest expression in heart, brain and kidney) and was originally cloned and characterized from human cardiac muscle (Komuro et al. 1992). Both SLC8A2) (Li et al. 1994) and SLC8A3 (Gabellini et al. 2002) are expressed in the brain.
In Rabbits, sorcin (SRI) activates SLC8A1, via the interaction of the respective Ca2+-binding domains (Zamparelli et al. 2010). Calmodulin (CALM1) binds to the cytoplasmic loop of NCX1 to negatively regulate exchange activity (Chou et al. 2015).
R-HSA-427910 (Reactome) Intracellular pools of Ca2+ serve as the source for inositol 1,4,5-trisphosphate (IP3) -induced alterations in cytoplasmic free Ca2+. In most human cells Ca2+ is stored in the lumen of the sarco/endoplastic reticulum by ATPases known as SERCAs (ATP2As). In platelets, ATP2As transport Ca2+ into the platelet dense tubular network. ATP2As are P-type ATPases, similar to the plasma membrane Na+ and Ca+-ATPases. Humans have three genes for SERCA pumps; ATP2A1-3. Studies on ATP2A1 suggest that it binds two Ca2+ ions from the cytoplasm and is subsequently phosphorylated at Asp351 before translocating Ca2+ into the SR lumen. There is a counter transport of two or possibly three protons ensuring partial charge balancing. Sarcolipin (SLN) can reversibly inhibit the activity of ATP2A1 by decreasing the apparent affinity of the ATPase for Ca2+ (Gorski et al. 2013) whereas activated Ca2+/CaM-dependent protein kinase II (CAMK2) and sorcin (SRI) can both stimulate ATP2A1-3 activity (Toyofuku et al. 1994, Matsumoto et al. 2005).
R-HSA-434798 (Reactome) Activation of Calcium-release-activated (CRAC) channels allows influx of calcium. The Orai component of CRAC is responsible for the selectivity of the channel, while the Stim component is responsible for activation.
R-HSA-5226904 (Reactome) Putative adenosylhomocysteinase 2 (AHCYL1 aka adenosylhomocysteine hydrolase-like protein 1) (Dekker et al. 2002) possesses 50% homology to adenosylhomocysteine hydrolase (AHCY), an enzyme important for metabolizing S-adenosyl-l-homocysteine. AHCYL1 can bind to the inositol 1,4,5-trisphosphate receptor (ITPR1) tetramer, suggesting that AHCYL1 is involved in modulating intracellular calcium release (Cooper et al. 2006).
R-HSA-5576895 (Reactome) Sodium channel proteins, subunit alpha (SCNAs) mediate the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na+ ions may pass in accordance with their electrochemical gradient. SCNA channels consist of an ion-conducting, pore-forming alpha-subunit regulated by one or more associated auxiliary subunits SCN1B, 2B, 3B and 4B. SCN1B and 3B are non-covalently associated with SCNA, while SCN2B is covalently linked by disulfide bonds.

SCNAs interact with cytosolic proteins that regulate channel trafficking and/or modulate the biophysical properties of the channels. Fibroblast growth factors (FGFs) are potent regulators of voltage-gated Na+ channels in adult ventricular myocytes and suggest that loss-of-function mutations in FGFs may underlie a similar set of cardiac arrhythmias and cardiomyopathies that result from SCN5A (aka Nav1.5) loss-of-function mutations. Ran guanine nucleotide release factor (RANGRF aka MOG1) is a critical regulator of sodium channel function in the heart and is thought to regulate the cell surface localization of SCN5A (Marfatia et al. 2001, Wu et al. 2008). Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D), as part of a heteromeric complex with CAMK2A, CAMK2B and CAMK2G can be activated by calmodulin/Ca2+ (CALM:4xCa2+) to then phosphorylate SNC5A at multiple sites, inactivating it (Ashpole et al. 2012).
R-HSA-5577050 (Reactome) Two potassium currents, IKs and IKr, provide the principal repolarising currents in cardiac myocytes for the termination of action potentials. Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1 aka Kv7.1) is the pore-forming alpha subunit of a complex also containing an ancillary protein from potassium voltage-gated channel subfamily E members (KCNE) that assemble as a beta subunit. The stoichiometry is believed to be 4 KCNQ1 subunits to 2 KCNE subunits (Plant et al. 2014). A-kinase anchor protein 9 (AKAP9) is an essential anchoring protein that binds to KCNQ1. Defects in KCNQ1 that disrupt this binding can result in type 1 long-QT syndrome (LQT1), a hereditary, potentially lethal arrhythmia syndrome (Chen et al. 2007). The AKAP9:KCNQ1:KCNE complex creates the slowly activating delayed rectifier cardiac potassium current IKs by the efflux of K+ from cardiac cells (Schroeder et al. 2000).
R-HSA-5577213 (Reactome) Voltage-dependent L-type calcium channels (LTCCs) transport Ca2+ into excitable cells. Isoforms CACNA1C, D, F and S form long-lasting (L-type) inward Ca2+ currents (ICaL) and play an important role in excitation-contraction coupling in the heart. LTCCs are multisubunit complexes consisting of alpha-1, alpha-2, beta, delta and gamma subunits in a 1:1:1:1:1 ratio (Brust et al. 1993). The alpha-2 and beta subunits in these complexes are chains of differing length cleaved from the same gene products (CACNA2D1, 2, 3 and 4), linked by a disulfide bond (Calderon-Rivera et al. 2012). Pore-forming alpha1 subunits are supported by the auxiliary alpha-2, delta and beta subunits which aid the membrane trafficking of the alpha1 subunit and modulate the kinetic properties of the channel (Klugbauer et al. 2003). In heart pacemaker cells, phase 0 of the action potential depends upon LTCC-mediated Ca2+ current rather than the fast Na+ current. In cardiac pacemaker cells, phase 1 is due to the closure of LTCCs (and rapid efflux of K+).
R-HSA-5577234 (Reactome) In phase 1 of the action potential, the fast Na+ channels are inactivated. This happens by net outward currents Ito1 and Ito2 caused by efflux of K+ and Cl- ions respectively. Potassium voltage-gated channel subfamily D members 1, 2 and 3 (KCND1, 2 and 3) are pore-forming (alpha) subunits of voltage-gated, rapidly inactivating A-type K+ channels (Isbrandt et al. 2000) that produce the Ito1 current. They may also contribute to the ISa current in neurons. KCND1 is functional as either a homo- or hetero-tetramer with KCND2 and/or KCND3. KCNDs associate with the regulatory subunits KCNIP1-4 (Scannevin et al. 2004, Pioletti et al. 2006). KCNIPs form homodimers and/or homotetramers (Lin et al. 2004). KCNIPs and KCNDs together modulate the density, inactivation kinetics and rate of recovery from inactivation of KCNDs (An et al. 2000, Nakamura et al. 2001, Shibata et al. 2003, Wang et al. 2007).
R-HSA-5577237 (Reactome) Two potassium currents, IKs and IKr, provide the principal repolarising currents in cardiac myocytes for the termination of action potentials. The potassium voltage-gated channel subfamily H member 2 (KCNH2 aka HERG) is the pore-forming alpha subunit of a stable complex with a regulating beta subunit of the potassium voltage-gated channel subfamily E family (KCNE). This stable complex creates the Kr current by the efflux of K+ (Macdonald et al. 1997, Abbott et al. 1999).
R-HSA-5578777 (Reactome) Force generation of the heart and calcium homeostasis are coupled in the myocardium. In the sarcoplasmic reticulum (SR), calcium stores provide the majority of calcium used in muscle contraction-relaxation. During relaxation, an ATP-dependent calcium pump (ATP2A2 aka SERCA) in the SR is essential for the recovery of calcium. The reuptake of calcium by ATP2A2 determines the rate of relaxation and the size of the calcium store available for subsequent contractions. In cardiac muscle, a second protein called phospholamban (PLN) acts as a reversible inhibitor of ATP2A2 and thereby modulates contractility in response to physiological factors. Defects in PLN are associated with lethal dilated cardiomyopathy in humans (Ceholski et al. 2012). PLN is a pentameric protein that, when phosphorylated, alleviates ATP2A2 inhibition and may stimulate SR calcium uptake in cardiomyocytes (Kaliman et al. 2005). Phosphorylation of PLN is mediated by myotonin-protein kinase (DMPK), a SR-bound homodimeric enzyme (Bush et al. 2000, Zhang & Epstein 2003).
R-HSA-5578783 (Reactome) Atrial natriuretic factor (NPPA(124-151) aka ANF) is a cardiac hormone essential for the regulation of blood pressure and promoting natriuresis, diuresis and vasodilation. In cardiac myocytes, NPPA is synthesised as an inactive precursor, pro-NPPA, that is converted to the biologically-active form by cleavage. Atrial natriuretic peptide-converting enzyme (CORIN) is the serine-type endopeptidase involved in NPPA processing. It is itself cleaved into 5 chains, with CORIN(802-1042) being the activated protease fragment (Yan et al. 2000, Knappe et al. 2003, Liao et al. 2007).
R-HSA-5578910 (Reactome) Potassium channels control neuronal excitability through influence over the duration, frequency and amplitude of action potentials. Potassium channels that are active at rest inhibit depolarization toward firing threshold, and thus suppress excitation. Conversely, potassium channels activated at depolarized potentials do not interfere with rise to threshold, but do facilitate recovery and repetitive firing. Tandem pore domain K+ channels (K2p) produce leak K+ current which stabilizes negative membrane potential and counter balances depolarization. These channels are regulated by voltage independent mechanisms such as membrane stretch, pH, temperature (Goldstein et al. 2005, Lotshaw 2007, Enyedi & Czirja 2010). Tandem pore domain K+ channels have been classified into six subfamilies; tandem pore domains in weak rectifying K+ channel (TWIK), TWIK-related K+ channel (TREK), TWIK-related acid-sensitive K+ channel (TASK), TWIK-related alkaline pH-activated K+ channel (TALK), tandem pore domain halothane-inhibted K+ channel (THIK), TWIK-releated spinal cord K+ channel). outwardly rectifying channel that is sensitive to changes in extracellular pH and is inhibited by extracellular acidification. Also referred to as an acid-sensitive potassium channel, it is activated by the anesthetics halothane and isoflurane.
R-HSA-5617178 (Reactome) Plasma membrane calcium-transporting ATPase 4 (ATP2B4 aka PMCA4) binds and inhibits cardiac neuronal nitric-oxide synthase (NOS1 aka nNOS, a powerful regulator of the beta-adrenergic contractile response in the heart) by changing local calcium concentration (Duan et al. 2013). Reduced nNOS activity leads to a reduction in cGMP which in turn results in the reduction of phosphodiesterase (PDE) activity. As a result, cAMP degradation is prevented, increasing protein kinase A (PKA) activity, which can lead to increased phosphorylation of proteins involved in the excitation-contraction coupling process such as cardiac phospholamban (PLN aka PLB) and of cardiac muscle troponin I (TNNI3 aka cTnI) (Mohamed et al. 2009).
R-HSA-5617179 (Reactome) Human cardiac troponin I (TNNI3) is known to be phosphorylated at multiple amino acid residue sites by several kinases. Protein kinase A (PRKACA) can phosphorylate serine 23 and 24 sites on TNNI3. Phosphorylation of TNNI3 reduces myofilament calcium sensitivity (Mittmann et al. 1990, Keane et al. 1997, Zhang et al. 2012). Defects in TNNI3 can cause a range of cardiomyopathies (Lu et al. 2013). The ATP2B4:NOS1 complex, via cAMP, increases PRKACA activity, thereby regulating the response of the heart to beta-adrenergic agonists.
R-HSA-5617182 (Reactome) Cardiac muscle phospholamban (PLN aka PLB) modulates cardiac contractility by inhibiting the sarcoplasmic reticulum calcium pump (ATP2A2 aka SERCA). This process is dynamically regulated by beta-adrenergic stimulation and phosphorylation of PLN. Protein kinase A (PRKACA) is able to phosphorylate PLN at serine 16, relieving its inhibition of ATP2A2 and modulating cardiac contractility (Glaves et al. 2011, Ceholski et al. 2012). The ATP2B4:NOS1 complex, via cAMP, increases PRKACA activity, thereby regulating the response of the heart to beta-adrenergic agonists.
R-HSA-5678261 (Reactome) ATP-sensitive inward rectifier potassium channel 11 (KCNJ11) is an inward rectifier potassium channel, favouring potassium flow into the cell rather than out of it. KCNJ11 can complex with ATP-binding cassette sub-family member 9 (ABCC9) to form cardiac and smooth muscle-type K+(ATP) channels. KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation (Babenko et al. 1998, Tammaro & Ashcroft 2007).
R-HSA-5692408 (Reactome) Atrial natriuretic peptide receptor 2 (NPR2) binds the C-type natriuretic peptide (NPPC, CNP) hormone. Natriuretic peptide hormones can stimulate natriuretic, diuretic, and vasorelaxant activity through the activation of guanylyl cyclases (Koller et al. 1991, Bartels et al. 2004).
R-HSA-6784598 (Reactome) Natriuretic peptides A (NPPA) is a hormone playing a key role in cardiovascular homeostasis through regulation of natriuresis, diuresis, and vasodilation. It specifically binds the atrial natriuretic peptide receptor 1 (NPR1) and stimulates its guanylate cyclase activity resulting in cGMP production (Koller et al. 1991, Pandey 2014).
R-HSA-936897 (Reactome) The sodium/potassium-transporting ATPase (ATP1A:ATP1B:FXYD) is composed of three subunits - alpha (catalytic part), beta and gamma. The trimer catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane, creating the electrochemical gradient which provides energy for the active transport of various nutrients.
Four human genes encode the catalytic alpha subunits, ATP1A1-4 (Kawakami et al, 1986; Shull et al, 1989; Ovchinnikov et al, 1988; Keryanov and Gardner, 2002). Defects in ATP1A2 cause alternating hemiplegia of childhood (AHC) (Swoboda et al, 2004). Another defect in ATP1A2 causes familial hemiplegic migraine type 2 (FHM2) (Vanmolkot et al, 2003). Defects in ATP1A3 are the cause of dystonia type 12 (DYT12) (de Carvalho Aguiar et al, 2004).

Three human genes encode the non-catalytic beta subunits, ATP1B1-3. The beta subunits are thought to mediate the number of sodium pumps transported to the plasma membrane (Lane et al, 1989; Ruiz et al, 1996; Malik et al, 1996). FXYD proteins belong to a family of small membrane proteins that are auxiliary gamma subunits of Na-K-ATPase. At least six members of this family, FYD1-4, 6 and 7, have been shown to regulate Na-K-ATPase activity (Geering 2006, Choudhury et al. 2007). Defects in FXYD2 are the cause of hypomagnesemia type 2 (HOMG2) (Meij et al, 2000). ATP1A1-4 and ATP1B1-4 play a minor role during phase 2, since they begin to restore ion concentrations. The high concentration of intracellular calcium starts contraction of those cells, which is sustained in the plateau phase.
RANGRFArrowR-HSA-5576895 (Reactome)
RYR

tetramer:FKBP1B tetramer:CASQ

polymer:TRDN:junctin
mim-catalysisR-HSA-2855020 (Reactome)
SCNAs:SCNBsmim-catalysisR-HSA-5576895 (Reactome)
SLC8A1,2,3mim-catalysisR-HSA-425661 (Reactome)
SLNTBarR-HSA-427910 (Reactome)
SRIArrowR-HSA-2855020 (Reactome)
SRIArrowR-HSA-425661 (Reactome)
STIM1:TRPC1mim-catalysisR-HSA-2089943 (Reactome)
TBX5:WWTR1:PCAFArrowR-HSA-2032800 (Reactome)
TBarR-HSA-2855020 (Reactome)
TNNI3R-HSA-5617179 (Reactome)
p-S16-PLN pentamerArrowR-HSA-427910 (Reactome)
p-S16-PLN pentamerArrowR-HSA-5578777 (Reactome)
p-S16-PLN pentamerArrowR-HSA-5617182 (Reactome)
p-S23,S24-TNNI3ArrowR-HSA-5617179 (Reactome)
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